BBS10 mutations in severe antenatal cases with severe cystic kidneys "Meckel-like" type. S. Audollent¹, L. Baala¹, R. Khaddour¹, J. Martinovic¹, A. Buenerd², G. Leichmeijer³, M. Le Merrer¹, A. Munnich¹, F. Encha-Razavi¹, M.C. Gubler⁴, M. Vekemans¹, T. Attié-Bitach¹. 1) Genetics, Inserm U-781, Paris, Paris, France; 2) Hopital Edward Herriot, Lyon, France; 3) Klinische Genetica en antropogenetica De Boelelaan, Amsterdam; 4) INSERM U-574 Hopital Necker, Paris France.
   Bardet-Biedl syndrome (BBS, OMIM 209900) is a multisystemic disorder characterized by progressive retinal dystrophy, postaxial polydactyly, obesity, hypogonadism, learning difficulty and renal dysfunction. Other manifestations include diabetes mellitus, neurological signs, heart disease, and hepatic fibrosis. The condition is largely genetically heterogeneous and 11 genes have been identified (BBS1-BBS11) thus far, mutations of BBS10 on chromosome 12q21.2 accounting for 30 % of cases. In addition, a complex epistatic inheritance has been established in this disorder, i.e. in some families, 3 mutations at 2 BBS loci are necessary for expression of the disease. We recently showed that fetuses with severe cystic kidneys were indeed prenatal forms of BBS. In the present study, we sequenced the BBS10 gene in 16 antenatal cases referred as Meckel-like. In 4 cases, we identified a recessive mutation at the BBS10 locus. Three fetuses had MKS kidney phenotype, whereas liver and brain were normal. As previously reported in foetal BBS cases, although the kidney histopathological findings were similar to MKS, no bile duct proliferation of liver was observed. Interestingly, one case had situs inversus and polysplenia suggesting a ciliary dysfunction. In another case, BBS genes screening identified a heterozygous BBS6 nonsens mutation in accordance with the multigenic inheritance of BBS. These results confirmed that the diagnosis of BBS is underdiagnosed antenatally, and should be systematically suspected in fetuses with severe cystic kidneys leading to oligoamnios and foetal or perinatal death. This study also confirms the high frequency of BBS10 mutations in BBS.